1. Field of the Invention
The present invention relates to a pharmaceutical agent comprising, as an active ingredient, natural calcitonin or a calcitonin derivative having a preventive effect on the onset of reflex sympathetic dystrophy developed after stroke.
2. Description of the Related Art
Reflex sympathetic dystrophy (hereinafter, also abbreviated to RSD) is a disease that is characterized by clinical symptoms such as pain, hyperalgesia, motor dysfunction, and dysautonomia and mainly triggered and developed by a limb trauma or surgical invasion. This disease is also frequently triggered and developed by a vascular disease in the trunk of the body, such as stroke or myocardial infarction. The post-stroke or post-myocardial infraction RSD is often developed as shoulder-hand syndrome (Ishibashi T., “Reflex sympathetic dystrophy”, Orthopedics—Approach to pain-5, Shoulder pain (supervised by Terayama K. and Kataoka O.), 183-197, 1998, Nankodo Co., Ltd.).
The shoulder-hand syndrome, which is a kind of RSD, causes RSD symptoms in a region spreading from the shoulder joint to the hand. Specifically, in many cases of RSD, shoulder pain occurs at first and pain and stiffness of fingers on flexion, swelling of the back of the hand, and hidrosis of the palm concur with or follow the shoulder pain (Ishibashi T., “Reflex sympathetic dystrophy”, Orthopedics—Approach to pain-5, Shoulder pain (supervised by Terayama K. and Kataoka O.), 183-197, 1998, Nankodo Co., Ltd.). Restrictions on person's movement in the upper limb caused by severe pain not only serve as a major hindrance factor for rehabilitation for overcoming paralysis associated with stroke or myocardial infraction but also have serious consequences to the QOL (quality of life) and ADL (activities of daily living) of patients (Yamaga M. et al., “Shoulder-hand syndrome”, Journal of pain and clinical medicine, 4 (2), 115-122, 2004). According to an epidemiological investigation, 10 to 20% of myocardial infraction patients (Ishibashi T., “Reflex sympathetic dystrophy”, Orthopedics—Approach to pain-5, Shoulder pain (supervised by Terayama K. and Kataoka O.), 183-197, 1998, Nankodo Co., Ltd. and Casale R. et al.: Increased sympathetic tone in the left arm of patients affected by symptomatic myocardial ischemia., Funct. Neurol., 4, 161-163, 1989.) and 23 to 70% of stroke patients (Daviet J C. et al.: Clinical factors in the prognosis of complex regional pain syndrome type I after stroke: a prospective study., Am. J. Phys. Med. Rehabil., 81, 34-39, 2002.) develop such shoulder-hand syndrome. This disease is resistant to therapy and leaves severe residual disabilities in many cases. Moreover, the disease tends to recur even when it is once remitted (Ishibashi T., “Reflex sympathetic dystrophy”, Orthopedics—Approach to pain-5, Shoulder pain (supervised by Terayama K. and Kataoka O.), 183-197, 1998, Nankodo Co., Ltd.).
Various therapeutic methods for RSD or shoulder-hand syndrome have been reported so far. However, a systematic therapeutic method remains to be established (Yamaga M. et al., “Shoulder-hand syndrome”, Journal of pain and clinical medicine, 4 (2), 115-122, 2004 and Yamaga M. et al., “Treatment of reflex sympathetic dystrophy”, Neurological Medicine, 54, 306-314, 2001). For example, low-dose steroid has been used on a clinical site and however, is restricted to short-time use for the purpose of circumventing various side effects (increased susceptibility to infection, bone density loss, abnormal glucose metabolism, stomach ulcer, etc.) attributed to the long-term administration of steroid. Thus, the long-term control of the disease is allegedly difficult. Another therapeutic method that is preferably performed is a nerve block in which local anesthesia is repetitively performed to sympathetic nerves. However, this method had many such problems that: tissues at the injection site adhere to each other and make a surgical operation difficult, if this site needs the surgical operation in the future; and the method has the risk of hematoma formation attributed to the block during treatment using drugs having an anticoagulant effect, such as ameliorants of cerebral circulation or thrombolytic agents.
Thus, RSD is exceedingly difficult to treat, once developed. Therefore, it is important to prevent the onset itself of RSD under the present circumstances.
For RSD triggered and developed by a trauma or surgical invasion, the preventive effect of vitamin C on the initial onset thereof (Zollinger P E. et al.: Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomized trial., Lancet, 354, 2025-2028, 1999.) and the preventive effect of natural calcitonin on the recurrence thereof (Kissling R O. et al.: Prevention of recurrence of Sudeck's disease with calcitonin., Rev. Chir. Orthop. Reparatrice Appar. Mot., 77, 562-567, 1991. and Marx C. et al.: Preventing recurrence of reflex sympathetic dystrophy in patients requiring an operative intervention at the site of dystrophy after surgery., Clin. Rheumatol., 20, 114-118, 2001.) have been demonstrated clinically. However, for RSD triggered and developed by a stroke, no pharmaceutical agent having a demonstrated safe and sufficient preventive effect has been reported, except for steroid, which is difficult to continuously administer for a long period. According to only one report, the onset of post-stroke RSD was reduced to 8 to 18.5% by restricted loads on the shoulder or paralyzed limbs (Kondo I. et al.: Protocol to prevent shoulder-hand syndrome after stroke., Arch. Phys. Med. Rehabil., 82, 1619-1623, 2001. and Braus D F. et al.: The shoulder-hand syndrome after stroke: a prospective clinical trial., Ann. Neurol., 36, 728-733, 1994.). However, this effect is still insufficient in light of the severity of this disease.
Natural calcitonin is a polypeptide of 32 amino acids secreted from thyroid cells in mammals. The natural calcitonin or a calcitonin derivative suppresses bone resorption by acting on osteoclasts and reduces the serum concentration of calcium. Therefore, these compounds have been used clinically as a therapeutic drug and/or a prophylactic drug for hypercalcemia or osteoporosis. Moreover, the natural calcitonin or the calcitonin derivative has been known widely to have an analgesic effect on a certain pain such as lumbar back ache associated with osteoporosis, cancer pain, or inflammatory pain and has also been reported to have a therapeutic effect on already developed RSD (Wade S. et al.: A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes., PAIN, USA, 73, 123-139, 1997. and Antonio Quatraro: Calcitonin in painful diabetic neuropathy., Lancet, 339, 746-747, 1992.).
On the other hand, with respect to the preventive effect of natural calcitonin on the onset of RSD, there has been reported a preventive effect on the recurrence thereof in patients having an anamnesis of RSD triggered and developed by a trauma or surgical invasion, as described above (Kissling R O. et al.: Prevention of recurrence of Sudeck's disease with calcitonin., Rev. Chir. Orthop. Reparatrice Appar. Mot., 77, 562-567, 1991. and Marx C. et al.: Preventing recurrence of reflex sympathetic dystrophy in patients requiring an operative intervention at the site of dystrophy after surgery., Clin. Rheumatol., 20, 114-118, 2001.). On the other hand, natural calcitonin has been reported to have no preventive effect on the initial onset of RSD in subjects having no anamnesis of RSD after a trauma or surgical invasion (Riou C. et al.: Can algodystrophy be prevented by thyrocalcitonin?, Rev. Chir. Orthop. Reparatrice Appar. Mot., 77, 208-210, 1991).
Under such circumstances, it has been strongly demanded to develop a novel pharmaceutical drug or a novel therapeutic method having a safe and sufficient preventive effect on RSD developed after stroke.
Thus, an object of the prevent invention is to provide a novel pharmaceutical agent having an excellent preventive effect on post-stroke RSD.